The article by Harper et al. is an important contribution to our understanding of the genetic architecture of social deficits common to developmental disorders such as schizophrenia and autism spectrum disorder. Harper et al. used a three-pronged approach to identify the role of Sept5, a gene located in the 22q11.2 deletion region, in social behavior. In a series of elegant experiments, they demonstrated that Sept5 deficiency disturbs social interactions in mice, and, conversely, that Sept5 overexpression increases levels of social interaction. By reducing stress in the mice through an environmental modification, they showed that increased levels of social behavior correspond to increased levels of expression of Sept5 protein in the amygdala. The studies from this group on Sept5 suggest that variability in social functioning related to changes in expression of Sept5 is likely to be mediated by both genetic background and environmental influences (Suzuki et al., 2009). Replication and extension of this study are needed to identify genetic modifiers and other environmental factors that may influence such social behavior.

The results of this study demonstrate the utility of using 22q11.2 deletion syndrome (22q11.2DS) as a model to understand the genetic underpinnings of clinical phenotypes—like social deficits—that are common to several neurodevelopmental disorders. Intellectual disabilities, anxiety, and schizophrenia are frequent manifestations of 22q11.2 deletion syndrome. All show incomplete penetrance and variable phenotypic severity in patients with 22q11.2DS. We note with interest the last paragraph of the study describing “synaptopathology” and the likelihood that the symphony of genes contributing to what we observe as individual neuropsychiatric disorders of varying ages of onset and composite symptoms may have common shared and non-shared genetic factors, including several genes in the 22q11.2 region. This may be why other multigene copy number variations (CNVs), such as 16p11.2 duplications, and 1q21.2 deletions and duplications, carry an increase risk for schizophrenia.